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Chinese Journal of Chemistry 2022年第11期40卷 1285-1292,I0002页

作者： Lei Wang Chenxi Du Hui Liu Weimin Qiu Xin Lu Yanyu Hu Yueqing Li Tianyu Sun Yao Chen Haopeng Sun School of Pharmacy China Pharmaceutical UniversityNanjingJiangsu 211198China Department of Natural Medicinal Chemistry China Pharmaceutical UniversityNanjingJiangsu 211198China School of Pharmacy Nanjing University of Chinese MedicineNanjingJiangsu 210023China

Butyrylcholinesterase(BChE)is regarded as a promising target for the treatment of Alzheimer's disease(AD),as its level significantly increases along with the progress of this disease.Therefore,the development of potent and high-affinity small-molecule BChE inhibi-tors may be a new strategy for the discovery of anti-AD drugs.However,the current Ellman's method is unable to evaluate the affinity of compounds with BChE,and has a few deficiencies in drug development.Herein,the first small-molecule fluorescence polarization(FP)probes for BChE were rationally designed based on a high affinity inhibitor.Studies indicated that probe F6 exhibited satisfactory fluorescence intensity and suitable fluorescent properties that were compatible with the filters in the FP system.Meanwhile,probe F6 exhibited potent binding affinity to BChE.It is feasible to be applied in detecting the affinity of non-fluorescent compounds to BChE,which lays a solid foundation for the development of small-molecule BChE inhibitors.At the same time,it also can be applied as a val-uable chemical tool for better understanding the molecular biological mechanism of BChE.

关键词： Butyrylcholinesterase Alzheimer's disease Fluorescent probes Inhibitors High-throughput screening

Acute effects of chlorpyryphos-ethyl and secondary treated effluents on acetylcholinesterase and Butyrylcholinesterase activities in Carcinus maenas

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Journal of Environmental Sciences 2009年第10期21卷 1467-1472页

作者： Jihene Ghedira Jamel Jebali Zied Bouraoui Mohamed Banni Lassaad Chouba Hamadi Boussetta Laboratory of Biochemical and Environmental Toxicology Higher Institute of Agriculture Chott-Mariem 4042 Sousse Tunisia Chemical Laboratory Higher Institute of Marine Sciences and Technology La Goulette Center 2060 Tunisia

The acute effects of commercial formulation of chlorpyrifos-ethyl （Dursban ） and the secondary treated industrial/urban effluent （STIUE） exposure on acetylcholinesterase （ACHE） and Butyrylcholinesterase （BuChE） activities in hepatopancreas and gills of Mediterranean crab Carcinus maenas were investigated. After 2 d of exposure to chlorpyriphos-ethyl, the AChE activity was inhibited in both organs at concentrations of 3.12 and 7.82 μg/L, whereas the BuCHE was inhibited only at higher concentration 7.82 μg/L of commercial preparation Dursban~. The exposure of crabs to Dursban （3.12 μg/L） showed a significant decrement of ACHE activity at 24 and 48 h, whereas the BuChE was inhibited only after 24 h and no inhibition for both enzymes was observed after 72 h. Moreover, a significant repression of AChE activity was observed in both organs of C. maenas exposed to 5% of STIUE. Our experiments indicated that the measurement of AChE activity in gills and hepatopancreas of C. maenas would be useful biomarker of organophosphorous （OP） and of neurotoxic effects of STIUE in Tunisia.

关键词： acetylcholinesterase Butyrylcholinesterase organophosphorous Dursban secondary treated industrial/urban effluent Carcinus maenas

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Inhibition of acetylcholinesterase and Butyrylcholinesterase by coptisine and its derivatives

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Inhibition of acetylcholinesterase and butyrylcholinesterase...

Prevalence of Wild-Type Butyrylcholinesterase Genotype in Patients with Alzheimer’s Dementia

中国药理学会第十一次全国学术会议

作者： ZHOU Dan,LIU Ai-lin,DU Guan-hua (Peking Union Medical College,Institute of Materia Medica,Chinese Academy of Medical Sciences, Beijing 100050,China)

OBJECTIVE Investigate the inhibitory effects of coptisine and its derivatives on acetylcholinesterase(AChE) and Butyrylcholinesterase(BuChE) to study the relationship between the bioactivities and the structures.METHODS AChE were derived from rat brain and BuChE were derived from human plasma,the inhibitory activities of the derivatives were detected through AChE inhibitor and BuChE inhibitor screening models and the 50%inhibitory concentration(IC) was calculated,the IC values of these compounds was used in the SAR analysis.RESULTS Coptisine exhibited moderate cholinesterases(ChEs) inhibitory effect with IC values of 25.74μmol·L for AChE and 4.62μmol·L for BuChE.Respectively,most of its derivatives exerted higher AChE inhibitory activities,J34720,J34734,J34725,J34726,J34728,J35247,J35366 exhibited inhibitory effects with IC values below 10μmol·L for ChEs,derivate J34726 exhibited good inhibitory effects with IC values 2.18μmol·L for AChE and 2.66μmol·L for BuChE.The Nitrogen and oxygen atoms present in the molecular were essential in the interaction of coptisine and AChE;derivative with alkyl side chain of C-13 had better AChE inhibitory effect and the effect increased along with the extension of carbon chain;the presence of side chain having 3-5 carbons decreased BuChE inhibitory effect,since the active site gorge of BuChE contained less aromatic amino acid residues.CONCLUSION AChE inhibitors are the most successful drugs for treatment of Alzheimer’ s disease(AD).Coptisine derivatives exhibited potent ChEs inhibitory activities,J34726 showed the most potent inhibitory activity among them.SAR study revealed that alkyl side chain at C-13 position strengthen the AChE inhibition.The findings of this study provide important information relating the chemical structure of coptisine derivatives to their inhibitory activity of ChE.This understanding would facilitate the structural modification and exploitation of coptisine derivatives as ChE inhibitor for AD treatment.

关键词： coptisine derivatives acetylcholinesterase Butyrylcholinesterase structure-activity relationship（SAR）

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World Journal of Neuroscience 2015年第3期5卷 175-179页

作者： Beate Mueller Georg Adler Novartis Pharma GmbH Nürnberg Germany Institut für Studien zur Psychischen Gesundheit Mannheim Germany

Approximately, two-thirds patients with Alzheimer’s disease (AD) are reported to have homozygous wild-type Butyrylcholinesterase (BuChE) gene expression. It is associated with a higher rate of hydrolysis of acetylcholine, which ultimately leads to increase in the levels of BuChE in advanced stages of the disease. Rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and BuChE, might be of additional benefit in patients with AD with wild-type BuChE allele.

关键词： Butyrylcholinesterase Alzheimer’s Disease Genotype

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

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Acta Pharmaceutica Sinica B 2023年第5期13卷 2152-2175页

作者： Damijan Knez Daniel Diez-Iriepa Mourad Chioua Andrea Gottinger Milica Denic Fabien Chantegreil Florian Nachon Xavier Brazzolotto Anna Skrzypczak-Wiercioch Ane Meden Anja Pilar Janko Kos Simon akelj Jure Stojan Kinga Saat Julia Serrano Ana Patricia Fernández Aitana Sánchez-García Ricardo Martínez-Murillo Claudia Binda Francisco López-Muoz Stanislav Gobec JoséMarco-Contelles University of Ljubljana Faculty of PharmacyLjubljana 1000Slovenia Laboratory of Medicinal Chemistry(Institute of Organic Chemistry CSIC)Madrid 28006Spain Departamento de Química Orgánicay Química Inorgánica Alcaláde HenaresMadrid 28871Spain Department of Biology and Biotechnology University of PaviaPavia 27100Italy Département de Toxicologie et Risques Chimiques Institut de Recherche Biomédicale des ArméesParis 91220France Department of Animal Anatomy and Preclinical Sciences University Centre of Veterinary Medicine JU-UAUniversity of Agriculture in KrakowKrakow 30-059Poland Institute of Biochemistry Faculty of MedicineUniversity of LjubljanaLjubljana 1000Slovenia Department of Pharmacodynamics Chair of PharmacodynamicsFaculty of PharmacyJagiellonian University Medical CollegeKrakow 30-688Poland Department of Translational Neurobiology Neurovascular Research GroupCajal Institute(CSIC)Madrid 28002Spain Biotechnology and Vegetal Biology Department Escuela Técnica Superior de Ingeniería AgronómicaAlimentaria y de BiosistemasUniversidad Politécnica de MadridMadrid 28040Spain Faculty of Health Camilo JoséCela University of Madrid(UCJC)Neuropsychopharmacology Unit“Hospital 12 de Octubre”Research InstituteMadrid 28692Spain

We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and Butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of neurodegenerative diseases.We identified QN 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde.Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition,yet unexpectedly showed potent inhibition of h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/L).The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding,which was further studied by enzyme kinetics.Compound 19 acted as a free radical scavenger and biometal chelator,crossed the blood—brain barrier,was not cytotoxic,and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease.In addition,in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination.Importantly,chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice,underscoring the disease-modifying effect of QN 19.

关键词： Quinolylnitrone Butyrylcholinesterase Monoamine oxidase B Alzheimer's disease Multifunctional ligands 6-Hydroxydopamine model Passive avoidance task Novel object recognition

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In vitro antioxidant assessment and a rapid HPTLC bioautographic method for the detection of anticholinesterase inhibitory activity of Geophila repens

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Journal of Integrative Medicine 2017年第3期15卷 231-241页

作者： Umesh Chandra Dash Atish Kumar Sahoo Regional Plant Resource Centre Medicinal & Aromatic Plant Division Forest & Environment DepartmentGovt. of Odisha Nayapalli Bhubaneswar 751015 India

OBJECTIVE： Geophila repens （L.） I. M. Johnst. （Rubiaceae）, a small, creeping, perennial herb, is claimed to have memory-enhancing property. The goal of this study was to assess its antioxidant and anticholinesterase activity and conduct a rapid bioautographic enzyme assay for screening acetylcholinesterase （ACHE） and Butyrylcholinesterase （BChE） inhibition of G. repens extracts. METHODS： Antioxidant activity of G. repens extracts was assessed by performing 1,1-diphenyl-2- picrylhydrazyl （DPPH）, nitric oxide （NO）, superoxide （SOD）, hydroxyl （OH） and total antioxidant capacity （TAC） assays. Anticholinesterase activity was investigated by quantifying the AChE and BChE inhibitory activities of chloroform （CGR）, ethyl acetate （EGR） and methanol （MGR） extract fractions from G. repens leaves. A rapid high-performance thin-layer chromatography （HPTLC） bioautographic method for the detection of AChE and BChE inhibition was performed. RESULTS： Among all extract fractions, EGR exhibited the highest half maximal inhibitory concentration （IC50） in DPPH, SOD, NO, OH and TAC assays, with IC50 of （38.33 ± 3.21）, （45.14 ±1.78）, （59.81± 1.32）, （39.45 ± 0.79） and （43.76 ± 0.81 ） μg/mL respectively. EGR displayed competitive, reversible inhibition of AChE and BChE activities with IC50 of （68.63±0.45） and （59.45 ±0.45）μg/mL, respectively. Total phenolic and flavonoids contents of EGR were found to be 360.42 mg gallic acid equivalents and 257.31 mg quercetin equivalents per gram of extract. Phytoconstituents of the EGR extract that were inhibitors of cholinesterase produced white spots on the yellow background of HPTLC plates in the bioautographic test. CONCLUSION： The results of this study revealed that phenols and flavonoids could be responsible for the antioxidant, anticholinesterase activities of G. repens.

关键词： Geophila repens Alzheimer disease acetylcholinesterase Butyrylcholinesterase fingerprint bioautographic phenolic, antioxidant

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Discovery of Tryptophan-tetrahydroisoquinoline Derivatives as Multifunctional Agents for Treatment of Alzheimer's Disease

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Chinese Journal of Chemistry 2022年第15期40卷 1821-1830页

作者： Xin Lu Yijun Liu Nan Qin Chenxi Du Yanyu Hu Yao Chen Haopeng Sun School of Pharmacy China Pharmaceutical UniversityNanjingJiangsu 211198China School of Pharmacy Nanjing University of Chinese MedicineNanjingJiangsu 210023China Department of Natural Medicinal Chemistry China Pharmaceutical UniversityNanjingJiangsu 211198China

Comprehensive Summary The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease(AD).We have identified tryptophan-tetrahydroisoquinoline derivatives as selective micro-nanomolar Butyrylcholinesterase(BChE)inhibitors.Molecular docking was applied for the rational design and binding mode analysis.They were defined according to their target inhibitory activity,low cytotoxicity,predicted permeability through the blood-brain barrier(BBB),and in vivo cognitive improvement.Additionally,the preferred compound showed ability to decrease self-induced Aβ1-42 aggregation and Aβ1-42 induced SH-SY5Y cell injury.Altogether,these factors indicated their potential as unique lead compounds for AD treatment.

关键词： Alzheimer's disease Butyrylcholinesterase Inhibitors Molecular modeling Biological activity

Phytochemical composition of Caesalpinia crista extract as potential source for inhibiting cholinesterase and β-amyloid aggregation: Significance to Alzheimer's disease

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Asian Pacific Journal of Tropical Biomedicine 2018年第10期8卷 500-512页

作者： Kolambe Rajappa Chethana Balappa Somappa Sasidhar Mahadeva Naika Rangappa Sangappa Keri Centre for Nano and Material Sciences Jain UniversityJain Global Campus Chemical Sciences and Technology Division CSIR-National Institute for InterdisciplinaryScience and Technology (CSIR-NIIST) Applied Nutrition Division Defence Food Research Laboratory

Objective: To screen plant extract fractions and elucidate the components present in Caesalpinia crista(C. crista) leaves for cholinergic and anti-amyloidogenic activities for the treatment of Alzheimer's diseases. Methods: This work has been carried out to study the action of C. crista extracts from nonpolar to polar solvents toward inhibition of oxidative stress, cholinergic and amyloidosis. The antioxidant activity was studied using DPPH total antioxidant assay; cholinergic assay by Ellman's method and anti-amyloidogenic assay by thioflavin-T fluorescence and transmission electron microscopy. Results: The quantification of polyphenols was carried out following C. crista methanolic extract(CCMeOH) HPLC fingerprinting, along with LC-MS and elucidated by MS LAMPS database. GC-MS of CCMeOH was screened for potential moieties. In vitro experimental results showed that the CCMe OH was potential extract that exhibited active inhibition of antioxidant property, cholinergic enzymes acetylcholinesterase and Butyrylcholinesterase. For anti-amyloidogenic evaluations, among all the extracts, the CCMe OH was found to have the potential toward inhibiting the oligomers, fibrillation of Aβ42 with good defibrillation of amyloid cascading properties. Conclusions: These results are also supported by the presence of polyphenols as the active ingredients. Multi-potent target drug therapy is a promising option in treating the Alzheimer's diseases. Methanolic extract of C. crista shows potential activity against cholinergic enzymes, Aβ42 aggregation with antioxidant activity.

关键词： Alzheimer’s disease Caesalpinia crista Acetylcholinesterase Butyrylcholinesterase β-Amyloid

Anti-epitope antibody, a novel site-directed antibody against human acetylcholinesterase

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Acta Pharmacologica Sinica 2004年第4期25卷 33-37页

作者： Xing-mei ZHANG, GangLIU, Man-ji SUN2 Institute of Pharmacology and Toxicology, Academyof MilitaryMedical Sciences, Beijing 100850, China Institute of Pharmacology and Toxicology Academy of Military Medical Sciences 北京 100850

AIM: To construct synthetic antigens using the epitope of human brain acetylcholinesterase (hbAChE) for induc- tion and detection of the specific antibody against the epitope, and to analyse the immunogenicity of the antibody. METHODS: The epitope (RTVLVSMNYR, amino acids 143-152) of hbAChEwas chemically synthesized, coupled with the carrier protein keyhole limpet hemocyanin (KLH) to construct an artificial immunogen (KLH-epitope), and injected into rabbits to raise antibody. The epitope conjugated with bovine serum albumin (BSA) was used as the detection antigen. The specificity of the antibody was tested by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The immunoreaction between the anti-recombinant human Butyrylcholinesterase (rhBChE) polyclonal antibody and the biotinylated-epitope was examined by indirect ELISA. RESULTS: The erythrocyte AChE, the hbAChE, rhBChE and the BSA-epitope all immunoreacted with the anti-epitope antibody against the epitope (143-152) of hbAChE, whereas the torpedo AChE did not. CONCLUSION: The hbAChE, the human erythrocyte AChE and hBChE share the conservative antigenic epitope RTVLVSMNYR, hence they can all immunoreact with the anti-epitope antibody. Since the epitope of hbAChE is less similar with the aligned amino acid sequences of AChE of Torpedo californica or Torpedo marmorata, there is not any immunoreactivity between them. The R, M, and N residues in the epitope seem to be necessary radicals for the conservation of antigenicity.

关键词： acetylcholinesterase Butyrylcholinesterase epitopes antibodies enzyme-linked immunosorbent assay Western blotting

Emerging links between type 2 diabetes and Alzheimer's disease

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World Journal of Diabetes 2015年第5期6卷 744-751页

作者： Gumpeny R Sridhar Gumpeny Lakshmi Gumpeny Nagamani Endocrine and Diabetes Centre Department of Obstetrics and GynecologyAndhra Medical College

Type 2 diabetes mellitus and Alzheimer's disease are both associated with increasing age,and each increases the risk of development of the other.Epidemiological,clinical,biochemical and imaging studies have shown that elevated glucose levels and diabetes are associated with cognitive dysfunction,the most prevalent cause of which is Alzheimer's disease.Cross sectional studies have clearly shown such an association,whereas longitudinal studies are equivocal,reflecting the many complex ways in which the two interact.Despite the dichotomy,common risk and etiological factors(obesity,dyslipidemia,insulin resistance,and sedentary habits) are recognized;correction of these by lifestyle changes and pharmacological agents can be expected to prevent or retard the progression of both diseases.Common pathogenic factors in both conditions span a broad sweep including chronic hyperglycemia per se,hyperinsulinemia,insulin resistance,acute hypoglycemic episodes,especially in the elderly,microvascular disease,fibrillar deposits(in brain in Alzheimer's disease and in pancreas in type 2 diabetes),altered insulin processing,inflammation,obesity,dyslipidemia,altered levels of insulin like growth factor and occurrence of variant forms of the protein Butyrylcholinesterase.Of interest not only do lifestyle measures have a protective effect against the development of cognitive impairment due to Alzheimer's disease,but so do some of the pharmacological agents used in the treatment of diabetes such as insulin(especially when delivered intranasally),metformin,peroxisome proliferator-activated receptors γ agonists,glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.Diabetes must be recognized as a risk for development of Alzheimer's disease;clinicians must ensure preventive care be given to control and postpone both conditions,and to identify cognitive impairment early to manage it appropriately.

关键词： Cognition Insulin resistance Insulin Butyrylcholinesterase Dementia